From genotype to phenotype: the differential expression of FGF, FGFR, and TGFbeta genes characterizes human cranioskeletal development and reflects clinical presentation in FGFR syndromes.

Mutations in the fibroblast growth factor receptor (FGFR) genes 1, 2, and 3 are causal in a number of craniofacial dysostosis syndromes featuring craniosynostosis with basicranial and midfacial deformity. Great clinical variability is displayed in the pathologic phenotypes encountered. To investigate the influence of developmental genetics on clinical diversity in these syndromes, the expression of several genes implicated in their pathology was studied at sequential stages of normal human embryo-fetal cranial base and facial ossification (n = 6). At 8 weeks of gestation, FGFR1, FGFR2, and FGFR3 are equally expressed throughout the predifferentiated mesenchyme of the cranium, the endochondral skull base, and midfacial mesenchyme. Both clinically significant isoforms of FGFR2, IgIIIa/c and IgIIIa/b, are coexpressed in maxillary and basicranial ossification. By 10 to 13 weeks, FGFR1 and FGFR2 are broadly expressed in epithelia, osteogenic, and chondrogenic cell lineages. FGFR3, however, is maximally expressed in dental epithelia and proliferating chondrocytes of the skull base, but poorly expressed in the osteogenic tissues of the midface. FGF2 and FGF4, but not FGF7, and TGFbeta1 and TGFbeta3 are expressed throughout both osteogenic and chondrogenic tissues in early human craniofacial skeletogenesis. Maximal FGFR expression in the skull base proposes a pivotal role for syndromic growth dysplasia at this site. Paucity of FGFR3 expression in human midfacial development correlates with the relatively benign human mutant FGFR3 midfacial phenotypes. The regulation of FGFR expression in human craniofacial skeletogenesis against background excess ligand and selected cofactors may therefore play a profound role in the pathologic craniofacial development of children bearing FGFR mutations.